Chronic myeloid leukemia (CML) is a hematopoietic malignancy characterized by an increase and unregulated growth of predominantly myeloid cells in the bone marrow, and their accumulation in the blood (1). A hallmark of CML is the Philadelphia chromosome resulting from a reciprocal translocation between the long arms of chromosomes 9 and 22 (2, 3). This chromosomal translocation leads to expression of BCR-ABL, an oncogenic fusion-protein with a constitutively activated ABL tyrosine kinase. BCR-ABL can transform myeloid progenitor cells and drives the development of 95% of CML cases. BCR-ABL promotes leukemogenesis by activating downstream signaling proteins that increase cell survival and proliferation (4). These pathways include, but are not limited to, the RAS/mitogen-activated protein kinase (RAF/MEK/ERK), phosphatidylinositol 3-kinase/AKT (PI3K/AKT), and JAK/STAT signaling cascades (5).
The first-line treatment for CML is imatinib mesylate (IM), which binds to the ABL kinase domain and inhibits phosphorylation of substrates (6). Although IM dramatically improves patient survival when used to treat early-stage disease, the drug is not curative. Resistance to IM can develop, especially in advanced-stage disease, leading to disease relapse and progression (7). Resistance to IM can result from multiple mechanisms that can be broadly classified as either BCR-ABL-dependent or BCR-ABL-independent (8). BCR-ABL-dependent resistance is most commonly due to the acquisition of point mutations in the ABL kinase domain that interfere with IM binding and subsequent kinase inhibition (9-11). However, in 50% or more of IM-resistant CML patients there is no mutation in BCR-ABL (12, 13) and the basis of such BCR-ABL-independent IM resistance is not understood.